Project Summary/Abstract In Parkinson's disease (PD), the loss of dopamine neurons is associated with marked motor impairments. Dopamine replacement therapy with levodopa is currently the most effective pharmacological approach, but chronic treatment is often complicated by the development of involuntary movements, known as levodopa- induced dyskinesia (LID). While the paucity of movement in PD is associated with a chronic loss of dopamine and LID is caused by chronic dopamine replacement with levodopa, the mechanisms underlying these pathological movements are poorly understood. To develop novel, targeted therapies, it is essential to identify the precise cellular and circuit alterations that result from chronic alterations in dopamine and drive motor deficits. The prevailing theory is that aberrant firing of neurons in the striatum, the major input nucleus of the basal ganglia, is a contributing mechanism. Integrating sensorimotor cortical and dopaminergic inputs, the striatum is poised to regulate normal and pathological movement by gating movement-related signals to downstream basal ganglia nuclei. Dopamine is hypothesized to modulate striatal activity via antagonistic control of the principal neurons of the striatum, medium spiny neurons (MSNs), exciting direct pathway neurons (dMSNs) and inhibiting indirect pathway neurons (iMSNs). The classical model of basal ganglia function builds upon this hypothesis, which predicts the loss of dopamine in PD causes an imbalance favoring iMSN activity, leading to motor deficits. This model also posits that LID results from an imbalance favoring dMSN activity, causing nonspecific action selection and involuntary movements. However, levodopa continues to relieve parkinsonian motor deficits even once LID develops, suggesting it may restore normal activity in some dMSNs, and induce aberrant activity in another subset of dMSNs, causing dyskinesia. Due to the dependence of LID on levodopa, this aberrant dMSN activity may be driven by dopamine-dependent alterations in striatal synaptic plasticity, such as excitatory synapses onto dMSNs. Using optogenetics and single-unit recordings in conjunction with a mouse model of PD and LID, the proposed experiments test these hypotheses in a pathway-specific manner. These experiments will be the first to directly test key tenets of the classical model in awake, behaving parkinsonian mice. Furthermore, dissecting subpopulations of dMSNs may lead to improved treatment for PD by identifying novel therapeutic targets.